Gemcitabine is a potent anticancer
drug approved for the treatment
of pancreatic, non-small-cell lung, breast, and ovarian cancers. The
major deficiencies of current gemcitabine therapy, however, are its
rapid metabolic inactivation and narrow therapeutic window. Herein,
we employed polyethylene glycol-b-distearoylphosphatidylethanolamine
(PEG-DSPE)/tocopheryl polyethylene glycol 1000 succinate (TPGS) mixed
micelles as a delivery system, to improve the pharmacokinetic characteristics
of gemcitabine and enhance its antitumor efficacy. By conjugating
stearic acid to gemcitabine and subsequently encapsulating stearoyl
gemcitabine (GemC18) within PEG-DSPE/TPGS mixed micelles, the deamination
of gemcitabine was delayed in vitro and in
vivo. Importantly, compared to free gemcitabine, GemC18-loaded
micelles pronouncedly prolonged the circulation time of gemcitabine
and elevated its concentration in the tumor by 3-fold, resulting in
superior antitumor efficacy in mice bearing human pancreatic cancer
BxPC-3 xenografts. Our findings demonstrate the promise of PEG-DSPE/TPGS
mixed micelles as a nanocarrier system for the delivery of gemcitabine
to achieve safer and more efficacious therapeutic outcomes.
In the present study, we synthesized a novel cationic copolymer composed of polyethylene glycol 5000 (PEG5K), vitamin E (VE), and diethylenetriamine (DET) at 1:4:20 molar ratio. The resulting PEG5K-VE4-DET20 copolymer formed nanoassemblies when mixed with the neutral PEG5K-VE4 copolymer at 1:8 weight ratio, which were investigated as the nanocarriers for combined delivery of paclitaxel and let-7b mimic. We found that the PEG5K-VE4-DET20 nanoassemblies could entrap paclitaxel for an extended period and burst release the drug in the presence of cathepsin B, demonstrating the biodegradability of the copolymers. At N/P ratio of 12:1, the PEG5K-VE4-DET20 nanoassemblies formed stable polyplexes with let-7b mimic, which were efficiently taken up by tumor cells and underwent endosomal escape. In non-small cell lung cancer A549 cells that harbor mutant KRAS, paclitaxel and let-7b mimic-loaded nanoassemblies (N-PTX/let-7b) markedly potentiated the cytotoxicity of paclitaxel, induced apoptosis, and diminished the invasiveness of tumor cells. In mice bearing subcutaneous A549 xenografts, intravenous administration of N-PTX/let-7b retarded tumor growth more efficaciously than Taxol. Our study demonstrates the promise of the PEG5K-VE4-DET20 nanoassemblies for concurrent delivery of hydrophobic drugs and miRNA mimics.
These results suggest that the crosslinked PEG114-VE4-TA4 nanocarrier system is a promising platform for the delivery of hydrophobic anticancer agents.
Heart failure (HF) is responsible for more 30-day readmissions than any other
condition. Minorities, particularly African American males (AAM), are at much
higher risk for readmission than the general population. In this study,
demographic, social, and clinical data were collected from the electronic
medical records of 132 AAM patients (control and intervention) admitted with a
primary or secondary admission diagnosis of HF. Both groups received
guideline-directed therapy for HF. Additionally the intervention group received
a pharmacist-led intervention. Data collected from these patients were used to
develop and validate a predictive model to evaluate the impact of the
pharmacist-led intervention, and identify predictors of readmission in this
population. After propensity score matching, the intervention was determined to
have a significant impact on readmission, as a significantly smaller proportion
of patients in the intervention group were readmitted as compared to the control
group (11.5% vs. 42.9%; p = .03). A predictive model for 30-day
readmission was developed using K-nearest neighbor (KNN) classification
algorithm. The model was able to correctly classify about 71% patients with an
AUROC of 0.70. Additionally, the model provided a set of key patient attributes
predictive of readmission status. Among these predictive attributes was whether
or not a patient received the intervention. A relative risk analysis identified
that patients who received the intervention are less likely to be readmitted
within 30 days. This study demonstrated the benefit of a pharmacist-led
intervention for AAM with HF. Such interventions have the potential to improve
quality of life for this patient population.
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